The goal of our program is to develop novel nontoxic approaches to cancer intervention. The prime focus is currently on: Modulators of Lipid Metabolism. (l) Phenyl-Fatty Acids. Phenylacetate (PA) and analogs were identified as a new class of nontoxic differentiation inducers. PA was shown to be selectively active against high-grade gliomas and hormone-refractory prostate carcinoma in vitro, in animal models, and in man. Potential mechanisms include: (a) inhibition of the MVA pathway of cholesterogenesis; (b) activation of PPAR, a nuclear receptor controlling fatty acid synthesis. (2) Vastatins. The hypolipidimic drug, lovastatin (inhibitor of HMG-CoA reductase), was found to affect glioma growth in vitro and in man. Combination of lovastin with PA (inhibits mevalonate-PP decarboxylase, i.e., downstream of HMG-CoA reductase) results in synergistic growth arrest of glioma cells. Hypomethylating Cytosine Analogs. 5-aza-2'deoxycytosine (DAC), an inhibitor of DNA methylation, was shown to activate critical cellular and viral genes silenced by methylation. These include: (a) VHL, a putative suppressor gene; (b) MAGE-1, a tumor rejection antigen; (c) EBV latent membrane proteins (LMP1 and EBNA-3). The antigens can evoke an Immune response against tumor cells, suggesting a potential role for DAC in combination with immunotherapy. Based on our preclinical findings, the following clinical trials are now being conducted: l. Phenylacetate phase I (CPB); 2. Phenylbutyrate phase I (CPB);3. Lovastatin phase I (CPB); 4. Lovastatin phase II in gliomas (MD Anderson); 5. DAC phase II in prostate (CPB); 6. DAC in renal cancer (Surgery Branch, NCI) It is hoped that the close interaction between our laboratory and the clinic will lead to significant developments in the field of cancer therapy and prevention.